DESCRIPTION Sexual dysfunction in women is primarily characterized by low levels of sexual arousal and desire. Because no effective treatments exist for disorders of sexual desire in women, the FDA was pressured to fast-track approval for the drug Addyi despite the absence of clinical evidence that the drug provided any therapeutic benefit. Underlying the inability to construct a rational approach to developing therapeutics for disorders of sexual desire in women is the lack of research on the mechanistic basis for female sexual desire in pre-clinical models. We have developed a Syrian hamster model of sexual desire that captures several essential elements needed to translate the findings to women. We developed a procedure to evaluate the rewarding properties of female sexual behavior, an element reported to be lacking in women with low sexual desire. Women with low sexual desire also do not initiate sexual contacts with their spouse or partner. In this regard we discovered an experimental approach to test the female hamster's willingness to initiate sexual contacts with a male. Based on these hamster studies we demonstrated that the rewarding consequences of sexual interactions with a male feed forward to increase the female's sexual contacts. We further identified the mesolimbic dopamine system, and prefrontal glutamatergic afferents, centered on the nucleus accumbens, as a critical neural node mediating the rewarding effects of sexual behavior in females. The research in this proposal takes three specific approaches to establish a programmatic understanding of the neurobiology of female sexual desire. In the first aim we will use inhibitory DREADDs to determine the relative contribution of dopamine and glutamate afferents to the nucleus accumbens to the development of sexual reward and initiation of sexual interactions with the male in our hamster model. We will also examine the contributions of these afferents to changes in dendritic spine morphology consequent to female sexual experience. The second aim takes a discovery approach to examining three possible intracellular signaling pathways mediating the effects of sexual experience on behavioral and morphological plasticity. The last aim will pharmacologically manipulate the individual signaling pathways to identify which of these pathways are potential molecular targets for therapeutic development to treat problems of sexual desire in women. Collectively this research will take a systematic approach to developing a neurobiology of female sexual desire with an eye to the rational development of effective therapies.